Frontotemporal dementia (FTD) is a neurological disorder characterized by profound personality changes, altered social behavior, and deterioration of executive functions. The second most common pathological entity of FTD is defined by the presence of cytoplasmic ubiquitin-immunoreactive inclusions, and is thus known as FTD-ubiquitinated (FTD-U). These inclusions, found primarily in the hippocampal dentate granule cells, may provide a window into the pathological mechanisms of FTD-U neurodegeneration but have, to date, been poorly characterized. Most significantly, the primary protein components of the inclusion bodies are unknown. Therefore, we propose to identify differentially expressed proteins in FTD-U inclusions that contribute to the underlying pathophysiologic pathways of the disease. First, a rigorous characterization of the cellular localization and ultrastructure of ubiquitin-positive inclusions will be conducted in Aim 1 using immunohistochemical and electron microscopy approaches. In Aim 2, the inclusions will be isolated using laser capture microdissection and proteomically profiled to identify proteins that mediate fundamentally important events in FTD-U pathogenesis. Finally, Aim 3 will focus on mechanistic contribution of these proteins to neurodegeneration seen in FTD-U. Specifically, the involvement of each identified inclusionspecific protein in cell death, protein aggregation, and the ubiquitin-proteasome system will be assessed. As the third most common cause of dementia, FTD accounts for up to 20% of all cases of dementia irrespective of age. Because of its predominantly presenile onset and invariable mortality, FTD carries extensive medical and socioeconomic costs. The characterization of the defining lesions of FTD-U, a common subtype of FTD, will shed light on the pathogenesis of this disease and provide novel therapeutic options aimed at slowing the progression and decreasing the mortality of this debilitating disease.